TY - JOUR
T1 - ACTIVATION OF GROUP-II METABOTROPIC GLUTAMATE RECEPTORS PROMOTES DNA DEMETHYLATION IN THE MOUSE BRAIN
JF - Molecular Pharmacology
JO - Mol Pharmacol
M3 - 10.1124/mol.110.070896
AU - Matrisciano, Francesco
AU - Dong, Erbo
AU - Gavin, David Peter
AU - Nicoletti, Ferdinando
AU - Guidotti, Alessandro
Y1 - 2011/04/19
UR - http://molpharm.aspetjournals.org/content/early/2011/04/19/mol.110.070896.abstract
N2 - Activation of group-II metabotropic glutamate receptors (mGlu2 and -3 receptors) has shown a potential antipsychotic activity, yet the underlying mechanism is only partially known. Altered epigenetic mechanisms contribute to the pathogenesis of schizophrenia and currently-used medications exert chromatin remodeling effects. Here, we show that systemic injection of the brain-permeant mGlu2/3 receptor agonist, LY379268 (0.3-1 mg/kg, i.p.) increased the mRNA and protein levels of Growth Arrest and DNA Damage 45-β (Gadd45-β), a molecular player of DNA demethylation, in the mouse frontal cortex and hippocampus. Induction of Gadd45-beta by LY379268 was abrogated by the mGlu2/3 receptor antagonist, LY341495 (1 mg/kg, i.p.). Treatment with LY379268 also increased the amount of Gadd45-β bound to specific promoter regions of reelin, brain-derived neurotrophic factor (BDNF), and glutamate decarboxylase-67 (GAD67). We directly assessed gene promoters methylation in control mice and in mice pretreated for seven days with the methylating agent methionine (750 mg/kg, i.p.). Both single and repeated injections with LY379268 reduce cytosine methylation in the promoters of the three genes, although the effect on the GAD67 was significant only in response to repeated injections. Single and repeated treatement with LY379268 could also reverse the defect in social interaction seen in mice pretreated with methionine. The action of LY379268 on Gadd45-β was mimicked by valproate and clozapine, but not haloperidol. These findings show that pharmacological activation of mGlu2/3 receptors has a strong impact on the epigenetic regulation of genes that have been linked to the pathophysiology of schizophrenia.
ER -